Chemical compounds

Abstract

A compound of formula (I) wherein: R1, R2, R3, R4, R5, R6 and R7 are as defined within; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof is described. The use of compounds of formula (I) in the production of an elevation of PDH activity in a warm-blooded animal such as a human being are also described. Pharmaceutical compositions, methods and processes for preparation of compounds of formula (I) are detailed.

What is claimed is:  
     
       1. A compound of formula (I):                    
       wherein: 
       R 1  and R 2  are each selected independently from hydrogen, phenyl optionally substituted by one or more Q, naphthyl optionally substituted by one or more Q, C 3-6 cycloalkyl optionally substituted by one or more Q, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl optionally substituted by one or more Q, R 8 T—, R 9 C 1-6 alkylT— and a heterocyclic group optionally substituted on a ring carbon by one or more Q and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D,  
       or R 1  and R 2  together with the nitrogen atom to which they are attached form a group Het which is optionally substituted on a ring carbon by one or more Q and wherein if group Het contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D;  
       R 3  and R 4  are independently C k alkyl optionally substituted by 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3;  
       or R 3  and R 4  together with the carbon atom to which they are attached, form a C m cycloalkyl ring optionally substituted by 1 to 2m-2 fluorine atoms wherein m is 3-5;  
       R 5  is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, cyano, nitro, C 2-6 alkenyloxy, trifluoromethylthio, halo, hydroxy, amino, N—(C 1-6 alkyl)amino, N—(C 1-6 alkyl)2amino, C 1-6 alkanoylamino, C 1-6 alkanoyl(N—C 1-6 alkyl)amino, C 1-6 alkylsulphonylamino, C 1-6 alkylsulphonyl(N—C 1-6 alkyl)amino, thiol, C 1-6 alkylsulphanyl, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, sulphamoyl, N—(C 1-6 alkyl)aminosulphonyl, N—(C 1-6 alkyl) 2 aminosulphonyl, carboxy, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkoxycarbonyl, formyl, C 1-6 alkanoyl, C 1-6 alkanoyloxy, C 2-6 alkenyl or C 2-6 alkynyl;  
       R 6  is hydrogen or Q;  
       R 7  is hydrogen, trifluoromethyl, C 1-4 alkyl, halo, hydroxy, trifluoromethoxy, cyano, C 1-4 alkoxy, formyl, C 1-4 alkanoyl, C 1-4 alkanoyloxy, amino, N—(C 1-4 alkyl)amino, N—(C 1-4 alkyl) 2 amino, C 1-4 alkanoylamino, C 1-4 alkanoyl(N—C 1-4 alkyl)amino, nitro, carboxy, carbamoyl, ureido, C 1-4 alkoxycarbonyl, thiol, C 1-4 alkylsulphanyl, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, sulphamoyl, N—(C 1-4 alkyl)aminosulphonyl, N—(C 1-4 alkyl) 2 aminosulphonyl, N′—(C 1-4 alkyl)ureido or N′—(C 1-4 alkyl) 2 ureido;  
       R 8  is C 1-6 alkyl optionally substituted by one or more R 10 , C 3-6 cycloalkyl optionally substituted by one or more R 10 , phenyl optionally substituted by one or more R 10 , naphthyl optionally substituted by one or more R 10  or a heterocyclic group optionally substituted on a ring carbon by one or more R 10  and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D;  
       R 9  is phenyl optionally substituted by one or more R 10 , naphthyl optionally substituted by one or more R 10  or a heterocyclic group optionally substituted on a ring carbon by one or more R 10  and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D;  
       R 10  is C 1-6 alkyl-M— optionally substituted by R 16 , halo, hydroxy, cyano, formyl, amino, nitro, carboxy, carbamoyl, thiol, sulphamoyl, phenyl optionally substituted by R 16 , a heterocyclic group optionally substituted on a ring carbon by R 16  wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D;  
       Q is C 1-6 alkyl-M— optionally substituted with one or more R 11 , C 2-6 alkenyl-M— optionally substituted by one or more R 11 , C 2-6 alkynyl-M— optionally substituted by one or more R 11 , R 13 —M—, hydroxy, halo, cyano, thiol, sulphamoyl, nitro, carboxy, amino, carbamoyl, formyl or ureido;  
       T is —O—, —C(O)—, —NH—,—N(N—C 1-6 alkyl)-, —C(O)NH—, —NHC(O)—, —C(O)N(N—C 1-6 alkyl)—, —N(N—C 1-6 alkyl)C(O)—, —SO 2 —, —C(S)—, —C(S)NH—, —NHC(S)—, —C(S)N(N—C 1-6 alkyl)- or —N(N—C 1-6 alkyl)C(S)—;  
       M is —(O—, —N(R 14 )—, —C(O)—, —N(R 14 )C(O)—, —C(O)N(R 14 )—, —S(O) n — wherein n is 0-2, —OC(O)—,—C(O)O—, —N(R 14 )C(O)O—, —OC(O)N(R 14 ), —C(S)N(R 14 )—, —N(R 14 )C(S)—, —SO 2 N(R 14 )—, —N(R 14 )SO 2 —, —N(R 14 )C(O)N(R 14 )—, —N(R 14 )C(S)N(R 14 )—, —SO 2 NHC(O)—, —SO 2 N(R 14 )C(O)—, —C(O)NHSO 2 —, —C(O)N(R 14 )SO 2 — or M is a direct bond;  
       D is C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulphonyl, C 1-6 alkoxycarbonyl, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N—(C 1-6 alkyl) 2 carbamoyl, benzoyl, (heterocyclic group)carbonyl, phenylsulphonyl, (heterocyclic group)sulphonyl, phenyl or a carbon linked heterocyclic group, and wherein any C 1-6 alkyl group may be optionally substituted by one or more R 11 , and wherein any phenyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R 10  and if a heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from E;  
       E is C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulphonyl, C 1-6 alkoxycarbonyl, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkoxyC 1-6 alkanoyl, phenylC 1-6 alkyl, benzoyl, phenylC 1-6 alkanoyl, phenylC 1-6 alkoxycarbonyl or phenylsulphonyl.  
       R 11  is hydroxy, nitro, cyano, thiol, halo, ureido, amino, N—(C 1-6 alkyl)amino, N—(C 1-6 alkyl) 2 amino, carboxy, C 1-6 alkoxy, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N—(C 1-6 alkyl) 2 carbamoyl, formyl, sulphamoyl, N—C 1-6 alkylaminosulphonyl, N—(C 1-6 alkyl) 2 aminosulphonyl, C 1-6 alkylsulphonylamino, C 1-6 alkanoylamino, C 1-6 alkylsulphanyl, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, phenyl optionally substituted by one or more R 10 , naphthyl optionally substituted by one or more R 10 , or a heterocyclic group optionally substituted on a ring carbon by one or more R 10  , and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D;  
       R 13  is phenyl optionally substituted by one or more R 10 , C 3-6 cycloalkyl optionally substituted by one or more R 10 , naphthyl optionally substituted by one or more R 10 , or a heterocyclic group optionally substituted on a ring carbon by one or more R 10  and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D;  
       R 14  is hydrogen or C 1-6 alkyl optionally substituted by one or more R 15  with the proviso that R 15  is not a substituent on the carbon attached to the nitrogen atom of M;  
       R 15  is halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, N—(C 1-6 alkyl)amino, N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, C 1-6 alkanoyl(N—C 1-6 alkyl)amino, C 1-6 alkylsulphonylamino, C 1-6 alkylsulphonyl(N—C 1-6 alkyl)amino, thio, C 1-6 alkylsulphanyl, C 1-6 alkylsuphinyl, C 1-6 alkylsulphonyl, sulphamoyl, N—(C 1-6 alkyl)aminosulphonyl, N—(C 1-6 alkyl) 2 aminosulphonyl, carboxy, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkoxycarbonyl, C 1-6 alkanoyl or formyl;  
       R 6  is hydroxy, halo, cyano, C 1-6 alkoxy, formyl, C 1-6 alkanoyl, C 1-6 alkanoyloxy, amino, N—(C 1-6 alkyl)amino, N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, C 1-6 alkanoyl(N—C 1-6 alkyl)amino, carboxy, carbamoyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulphanyl, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, sulphamoyl, N—(C 1-6 alkyl)aminosulphonyl or N—(C 1-6 alkyl) 2 aminosulphonyl;  
       and wherein if one of R 5 , R 6  and R 7  is hydrogen the others cannot be hydrogen; 
       or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
     
     
       2. A compound of formula (I) according to  claim 1  wherein R 1  and R 2  are each selected independently from hydrogen, phenyl optionally substituted by one or more Q, C 3-6 cycloalkyl optionally substituted by one or more Q, C 1-6 alkyl optionally substituted by one or more Q and a heterocyclic group optionally substituted on a ring carbon by one or more Q, 
       or R 1  and R 2  together with the nitrogen atom to which they are attached form a group Het which is optionally substituted on a ring carbon by one or more Q; wherein Q is selected from hydroxy, acetamido, acetyl, dimethylamino, methoxy or methyl;  
       or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
     
     
       3. A compound of formula (I) according to  claim 1  wherein 
       R 1  and R 2 are each selected independently from hydrogen, phenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-acetylphenyl, 4-acetamidophenyl, 4-dimethylaminophenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, methyl, ethyl, isopropyl, 4-hydroxycyclohexyl, 1-methyl-2-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, pyrid-3-yl and 5-methylpyrid-2-yl, 2-methoxypyrid-5-yl,  
       or R 1  and R 2  together with the nitrogen atom to which they are attached form 3-hydroxypyrrolidin-1-yl, 3-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl or morpholino;  
       or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
     
     
       4. A compound of formula (I) according to  claim 1  wherein one of R 3  and R 4  is methyl and the other is trifluoromethyl; 
       or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
     
     
       5. A compound of formula (I) according to  claim 1  wherein R 5  is selected from chloro or methoxy; 
       or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
     
     
       6. A compound of formula (I) according to  claim 1  wherein R 6  is selected from hydrogen, chloro, iodo, methylsulphanyl or methyl; 
       or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
     
     
       7. A compound of formula (I) according to  claim 1  wherein R 7  is hydrogen or methoxy; 
       or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
     
     
       8. A compound of formula (I) selected from: 
       (R)-N-[2,3-dichloro-4-(methylaminosulphonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;  
       (R)-N-{2,3-dichloro-4-[(1-methyl-2-hydroxyethylamino)sulphonyl]phenyl}-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;  
       (R)-N-[2-chloro-3-methyl-4-((S)-2-hydroxypropylamino-sulphonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;  
       (R)-N-[2-chloro-3-methyl-4-((R,S)-2-hydroxypropylaminosulphonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;  
       (R)-N-{2-chloro-3-methyl-4-[(3-hydroxyprop-2-ylamino)sulphonyl]phenyl}-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;  
       (R)-N-[2,3-dichloro-4-((S)-3-hydroxyprop-2-ylamino-sulphonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;  
       (R)-N-[2-chloro-3-methyl-4-((S)-2-hydroxypropylamino-sulphonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;  
       (R)-N-[2-chloro-3-methyl-4-((R)-2-hydroxypropylamiio-sulphonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;  
       or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
     
     
       9. A process for preparing a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, which process (in which variable groups are as defined in  claim 1  for formula (I) unless otherwise stated) comprises of: 
       (a) deprotecting a protected compound of formula (II):                    
        where Pg is an alcohol protecting group;  
       (b) coupling an aniline of formula (III):                    
        with an acid of formula (IV):                    
        wherein G is a hydroxyl group;  
       (c) coupling an aniline of formula (III) with an activated acid derivative of formula (IV) wherein G is a hydroxyl group which may be protected as an ester, ether or silyl ether;  
       (d) reacting a compound of formula (V):                    
        where K is a leaving atom or group and G is a hydroxyl group which may be protected as an ester; with an amine of formula (VI):  
       
         
           R 1 R 2 NH  (IV);  
         
       
       and thereafter if necessary:  
       i) converting a compound of the formula (I) into another compound of the formula (I);  
       ii) removing any protecting groups; or  
       iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.  
     
     
       10. A pharmaceutical composition which comprises a compound of formula (I) according to any one of claims  1 - 8 , or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
       11. A method for the treatment of a disease state associated with reduced PDH activity, said method comprising administering to a warm-blooded animal in need thereof a PDH activity-elevating amount of a compound of the formula (I) according to any one of claims  1 - 8 , or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. 
     
     
       12. The method of  claim 11  wherein said disease state is selected from the group consisting of diabetes mellitus, obesity and lactic acidaemia. 
     
     
       13. The method of  claim 11  wherein said disease state is diabetes mellitus.